Genetic susceptibility factors determine the propensity of individuals and populations to serious chronic diseases such as type 2 diabetes, asthma, inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and atherosclerosis. It is also clear that environmental factors are probably as important as the patient's genetic makeup in determining the risk, development and progression of these major, currently incurable diseases. However, it is not yet understood how environmental and genetic factors communicate and cooperate in the pathogenic process. We propose that stress activated protein kinases, including JNK and ZKK, provide a crucial link between the environment and the genome and are important contributors to the etiology of major degenerative, inflammatory and metabolic diseases. Although this hypothesis is supported by circumstantial and preliminary evidence it requires critical and rigorous examination. We propose to use mutant mice (both constitutive and conditional knockouts, as well as knockin mutants) lacking JNK1, JNK2 or IKK-beta (the crucial catalytic subunit of the IKK complex) to evaluate the role of these protein kinases in development of obesity-induced insulin resistance and type 2 diabetes, asthma and chronic airway remodeling, and IBD. Both genetic and environmentally induced mouse models for these diseases will be used. In addition to examining the role of JNK and IKK in disease etiology and pathogenesis via loss-of-function mutations we will examine whether the constitutive activation of IKK, achieved via a novel gain-of-function approach, is sufficient to trigger the pathogenic mechanism or increase sensitivity to environmental factors. In the case of type 2 diabetes the biochemical mechanisms through which JNK and IKK contribute to disease development will be investigated in detail. Collectively, these studies will provide a molecular framework for understanding how environmental factors communicate with genetic determinants to elicit major degenerative, metabolic and chronic inflammatory diseases.